Project Summary Candidate Dr Madden is a senior lecturer at the University of Cape Town who is committed to a research career in South Africa, with the career vision of leading interdisciplinary research to understand pain mecha- nisms and develop scale-able, focused treatments that safely and effectively relieve pain in resource-limited settings. With 5 years of dedicated research time, she will be able to implement her systematic career devel- opment plan to (1) deepen her understanding of advanced methodology and expertise in research program management, (2) expand her knowledge of HIV, immunology and psychosocial influences on pain, and (3) gain valuable first-hand experience in conducting community-based research in South Africa. This will de- velop her as the first South African cross-disciplinary expert in the interactions between psychology, immu- nology and pain in HIV. The career development plan is built around coordinated, cross-disciplinary training at the University of Cape Town, Harvard University and University of Michigan; hands-on research in South Africa, and close mentorship from a carefully selected team of highly experienced research scientists. Research Living with HIV is frequently accompanied by persistent pain and psychosocial distress (PSD). Most HIV-related pain is not explained by peripheral neuropathy, but resembles complex chronic pain condi- tions in which the immune system has been found to have an exaggerated response to provocation (inflam- matory reactivity). PSD is known to contribute to immune dysregulation and to pain. One pathway by which PSD may influence HIV-related pain is via inflammatory reactivity (IR) ? but this has not been established. In this Research Project, Phase 1 (Specific Aim 1) aims to characterize the relationships between PSD, IR, central sensitization and persistent pain in HIV. It will use a cohort study with baseline measures from HIV+ people with/without persistent pain (2 groups), and longitudinal follow-up of a subsample of participants from each group over a 6-month period. Mediation analysis will clarify whether IR represents a pathway for the influence of PSD on HIV-related pain; group comparisons will contrast IR and central sensitization between those with and without persistent pain; generalized mixed effect models will examine fluctuations in PSD, IR and pain over time in each group. This will be the first characterization of the associations between psycho- social distress, inflammatory reactivity, central sensitization and HIV-related pain. Phase 2 (Specific Aim 2) aims to develop and determine the feasibility and acceptability of a pragmatic, scale-able, coping-focused intervention to decrease distress and pain in people with HIV in South Africa. The intervention will be devel- oped, for non-specialist delivery, during a culturally secure, stepwise formative process including community and receiver engagement. A small open pilot trial (n = 10) that incorporates iterative revision of intervention content and delivery will be used to test intervention feasibility and acceptability and to troubleshoot imple- mentation and assessment procedures to inform future, fully powered clinical testing.